title: Total synthesis and study of 6-deoxyerythronolide B by late-stage C-H oxidation.
abstract: Among the frontier challenges in chemistry in the twenty-first century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. Oxidation reactions of C-H bonds, particularly when applied at late stages of complex molecule syntheses, hold special promise for achieving both these goals. Here we report a late-stage C-H oxidation strategy in the total synthesis of 6-deoxyerythronolide B (6-dEB), the aglycone precursor to the erythromycin antibiotics. An advanced intermediate is cyclized to give the 14-membered macrocyclic core of 6-dEB using a late-stage (step 19 of 22) C-H oxidative macrolactonization reaction that proceeds with high regio-, chemo- and diastereoselectivity (>40:1). A chelate-controlled model for macrolactonization predicted the stereochemical outcome of C-O bond formation and guided the discovery of conditions for synthesizing the first diastereomeric 13-epi-6-dEB precursor. Overall, this C-H oxidation strategy affords a highly efficient and stereochemically versatile synthesis of the erythromycin core.
authors.affiliation: Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, 61801, USA.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Stang
authors.forename: M Christina
authors.initials: MC
authors.lastname: White
mesh_terms: D018360:Crystallography, X-Ray; D003500:Cyclization; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013237:Stereoisomerism
chemical_list: C034277:6-deoxyerythronolide B; D004917:Erythromycin